Type .beta. transforming growth factor (TGF-.beta.) is a multi-functional, hormonally active polypeptide that is synthesized by many cell types. Virtually all cells have receptors for TGF-.beta.. See, generally, M. B. Sporn, et al., Transforming Growth Factor-.beta.: Biological Function and Chemical Structure, Science, Vol. 233, p. 532-534 (1986); J. Massague, The Transforming Growth Factors, Trends in Biochem. Sci., Vol. 10, p. 239-240 (1985a). Though TGF-.beta. was first identified by its ability to cause phenotypic transformation of rat fibroblasts, it is now recognized as having regulatory actions in a wide variety of both normal and neoplastic cells. TGF-.beta. influences the rate of proliferation of many cell types, acting as a growth inhibitor and also controlling processes of adipogenesis, myogenesis, chondrogenesis, osteogenesis, epithelial cell differentiation and immune cell function. Increased expression of fibronectin, type I collagen and probably other extracellular matrix compoments is a widespread early response of cells to TGF-.beta.. Alterations in the architecture of the extracellular matrix induced by TGF-.beta. could be involved in regulating the expression of specific phenotypes by this factor, while certain effects of TGF-.beta. on cell proliferation may be secondary to elevated expression of mitogenically active polypeptides.
Recently it has been discovered that TGF-.beta. is prototypic of a family of homologous polypeptides that control the development of tissues in organisms from humans to Drosophila. This family includes various inhibins and activins which regulate the ability of cultured pituitary cells to release follicle stimulating hormone, (see, e.g., A. Mason, et al., Structure of Two Human Ovarian Inhibins, Biochem. Biophys. Res. Commun., Vol. 135, p. 957-964 (1986)), the Mullerian inhibiting substances (MIS) which inhibits development of the Mullerian duct in mammalian male embryos, (see, R. Cate, et al., Isolation of the Bovine and Human Genes for Mullerian Inhibiting Substance and Expression of the Human Gene in Animal Cells, Cell, Vol. 45, p. 685-698 (1986)), and the transcript of the decapentaplegic gene complex which is critical for the development of Drosophila, (see, R. Padgett, et al., A Transcript From a Drosophila Pattern Gene Predicts a Protein Homologous to the Transforming Growth Factor .beta. Family, Nature, Vol. 325, p. 81-84 (1986). The bioactive domains corresponding to inhibins, activins, MIS and DPP-C transcript share only about 25% to 35% amino acid sequence identity with TGF-.beta..
Three structurally distinct cell surface glycoproteins have been identified that specifically bind TGF-.beta. with affinity constants in the picomolar range. J. Massague, The Transforming Growth Factors, Trends in Biochem. Sci., Vol. 10, p. 239-40 (1985). Since many cell lines display all three types of putative TGF-.beta. receptors, it is possible that this family of TGF-.beta. receptors might interact with a family of TGF-.beta.-related polypeptides in a situation similar to that which exists among the receptors for other families of hormonally active agents.
TGF-.beta. is highly conserved among mammalian species; mouse and human TGF-.beta. differ in amino acid sequence by a single amino acid. To date, TGF-.beta., a 25 kDa protein, has been thought to be present in mammals in a single form, a homodimer of two 12.5 kDa chains linked by disulfide bonds. But cf. EPO application 85304848.6, "Polypeptide Cartilage-Inducing Factors Found in Bone" (Inventor: S. Seyedin et al.) (describes two forms of cartilage-inducing factor, CIF-A and CIF-B, each of which is a homodimer, the two forms having different amino acid sequences) with S. Seyedin et al., "Cartilage-inducing Factor-A: Apparent Identity to Transforming Growth Factor-.beta.," J. of Biol. Chem. Vol. 261, p. 5693-95 (1986).